Savella

5 WARNINGS AND PRECAUTIONS Suicidality : Monitor for worsening of depressive symptoms and suicide risk ( 5.1 ). Serotonin Syndrome : Increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue SAVELLA and any other serotonergic agents, and initiate supportive treatment ( 5.2 ). Elevated B lood P ressure and H eart R ate : SAVELLA may increase blood pressure and heart rate. Measure blood pressure and heart rate prior to initiating treatment with SAVELLA and monitor periodically throughout treatment ( 5.3 , 5.4 ). Seizures : Cases have been reported with SAVELLA therapy. Prescribe SAVELLA with care in patients with a history of seizure disorder ( 5.5 ). Hepatotoxicity : SAVELLA may cause elevations of ALT and AST. Avoid concomitant use of SAVELLA in patients with substantial alcohol use or chronic liver disease ( 5.6 ). Discontinuation : Withdrawal symptoms have been reported in patients when discontinuing treatment with SAVELLA. A gradual dose reduction is recommended ( 5.7 ). Increased Risk of Bleeding : SAVELLA may increase the risk of bleeding events. Caution patients about the risk of bleeding associated with the concomitant use of SAVELLA and NSAIDs, aspirin, or other drugs that affect coagulation ( 5.9 ). History of Dysuria : Male patients with a history of obstructive uropathies may experience higher rates of genitourinary adverse events ( 5.11 ). Sexual Dysfunction : SAVELLA use may cause symptoms of sexual dysfunction ( 5.12 ). 5.1 Suicide Risk SAVELLA is a selective serotonin and norepinephrine re-uptake inhibitor (SNRI), similar to some drugs used for the treatment of depression and other psychiatric disorders. Patients, both adult and pediatric, with depression or other psychiatric disorders may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking these medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants, including drugs that inhibit the reuptake of norepinephrine and/or serotonin, may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. In the placebo-controlled clinical trials of adults with fibromyalgia, among the patients who had a history of depression at treatment initiation, the incidence of suicidal ideation was 0.5% in patients treated with placebo, 0% in patients treated with SAVELLA 100 mg/day, and 1.3% in patients treated with SAVELLA 200 mg/day. No suicides occurred in the short-term or longer-term (up to 1 year) fibromyalgia trials. Pooled analyses of short-term placebo-controlled trials of drugs used to treat depression (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with these drugs compared to placebo in adults beyond age 24; there was a reduction in suicidality risk with antidepressants compared to placebo in adults age 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 drugs used to treat depression in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug versus placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1 . Table 1: Risk Differences (Drug – Placebo) in the number of Cases of Suicidality, per 1000 patients treated Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated < 18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥ 65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with drugs inhibiting the reuptake of norepinephrine and/or serotonin for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, have been reported in adult and pediatric patients being treated with drugs inhibiting the reuptake of norepinephrine and/or serotonin for major depressive disorder as well as for other indications, both psychiatric and non-psychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who may experience worsening depressive symptoms, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe or abrupt in onset, or were not part of the patient’s presenting symptoms. If the decision has been made to discontinue treatment due to worsening depressive symptoms or emergent suicidality, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can produce withdrawal symptoms [see Dosage and Administration ( 2.1 , 2.4 ), Warnings and Precautions ( 5.7 )] . Families and caregivers of patients being treated with drugs inhibiting the reuptake of norepinephrine and/or serotonin for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for SAVELLA should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. 5.2 Serotonin Syndrome Selective-serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), including SAVELLA, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, tramadol, meperidine, methadone, lithium, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin i.e., MAOIs [see Contraindications ( 4 ), Drug Interactions ( 7 )] . Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of SAVELLA with MAOIs is contraindicated. In addition, do not initiate SAVELLA in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking SAVELLA, discontinue SAVELLA before initiating treatment with the MAOI [see Contraindications ( 4.1 ), Dosage and Administration ( 2.5 , 2.6 ) , Drug Interactions ( 7.1 ) ] . Monitor all patients taking SAVELLA for the emergence of serotonin syndrome. Discontinue treatment with SAVELLA and any concomitant serotonergic agents immediately if the above events occur and initiate supportive symptomatic treatment. If concomitant use of SAVELLA with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. 5.3 Elevated Blood Pressure A double-blind, placebo-controlled ambulatory blood pressure monitoring (ABPM) study was conducted to evaluate the effects of milnacipran (up to 200 mg/day) on blood pressure in 321 fibromyalgia patients. Among fibromyalgia patients who were normotensive at baseline, an analysis of the blood pressure findings demonstrated a substantially higher proportion of SAVELLA-treated patients had a hypertensive blood pressure measurement at the Week 4, 50 mg BID steady state visit (17.7% [n=21/119]) and the Week 7, 100 mg BID steady state visit (14.3% [n=15/105]) as compared to placebo-treated patients (3.7% [n=2/54] and 0% [0/49] at the Week 4 and Week 7 visits, respectively). Hypertension was defined as mean systolic blood pressure (SBP) ≥140 mmHg and change from baseline in mean SBP ≥10 mmHg or mean diastolic blood pressure (DBP) ≥90 mmHg and change from baseline in mean DBP ≥5 mmHg for the 12-hour period post AM study drug measurement at that visit. Furthermore, 1.9% (4/210) of SAVELLA-treated and 0.9% (1/111) of placebo patients discontinued treatment for increases in blood pressure. The increased risk of blood pressure measurements in the hypertensive range in SAVELLA-treated patients is supported by substantial increases in mean SBP and DBP measurements observed in the ABPM study. Table 2 shows that, following treatment with SAVELLA 50 mg BID for three weeks in patients who were normotensive at baseline, the mean increase from baseline was 5 mmHg in systolic blood pressure (SBP) and diastolic blood pressure (DBP). After further treatment with SAVELLA 100 mg BID for two weeks, the mean increase from baseline in SBP and DBP was 6 mmHg. Similar elevations occurred in SAVELLA-treated patients who were hypertensive at baseline. Table 2: Mean (Standard Error) Change from Baseline in Mean 24-hour Systolic and Diastolic Blood Pressure (mmHg) of Milnacipran or Placebo following 4 Weeks of Treatment (50mg BID) and a Subsequent 2 Weeks of Treatment (100mg BID) Normotensive Hypertensive n Systolic Diastolic n Systolic Diastolic Placebo 39 0(2) -1(1) 50 0(2) 0(2) 50 mg BID * 92 5(1) 5(1) 84 5(2) 4(1) Placebo 37 0(2) -1(1) 47 -1(2) 0(1) 100 mg BID ^ 82 6(1) 6(1) 80 5(2) 4(1) *Blood pressure measurements made after 3 weeks of milnacipran 50mg BID ^Blood pressure measurements made after 2 weeks of milnacipran 100mg BID Similar patterns of treatment-emergent blood pressure elevations were observed in Phase 3 and clinical pharmacology studies as manifested by an increased risk of new onset hypertension or substantial increases in end of study blood pressure measurements in patients with hypertension at baseline ( Table 3 ). Table 3: Blood pressure changes in Phase 3 randomized controlled trials Milnacipran 50 mg BID Milnacipran 100 mg BID Placebo FM patients normotensive at baseline who became hypertensive (defined as SBP ≥ 140 mmHg or DBP ≥ 90 mmHg on three consecutive post-baseline visits) 20% 17% 7% FM patients with sustained increases in SBP (increase of ≥ 15 mmHg on three consecutive post-baseline visits) 9% 6% 2% FM patients with sustained increases in DBP (increase of ≥ 10 mmHg on three consecutive post-baseline visits) 13% 10 % 4% FM patients hypertensive at baseline who had increases in SBP ≥ 15 mmHg at end of study 10% 7% 4% FM patients hypertensive at baseline who had increases in DBP ≥ 10 mmHg at end of study 8% 6% 3% Sustained increases in blood pressure may have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported. Concomitant use of SAVELLA with drugs that increase blood pressure and heart rate has not been evaluated and such combinations should be used with caution [see Drug Interactions ( 7 )] . Effects of SAVELLA on blood pressure in patients with significant hypertension or cardiac disease have not been systematically evaluated. SAVELLA should be used with caution in these patients. Measure blood pressure prior to initiating treatment and periodically monitor blood pressure throughout SAVELLA treatment. Treat pre-existing hypertension and other cardiovascular disease before starting therapy with SAVELLA. For patients who experience a sustained increase in blood pressure while receiving SAVELLA, either reduce the dose or discontinue treatment with SAVELLA if clinically warranted. 5.4 Elevated Heart Rate A double-blind, placebo-controlled ABPM study was conducted to evaluate the effects of milnacipran (up to 200 mg/day) on blood pressure in 321 fibromyalgia patients [see Warnings and Precautions ( 5.3 )] . Information on heart rate was also collected. Following treatment with SAVELLA 50mg BID for three weeks in patients who were normotensive at baseline, the mean increase in mean 24-hour heart rate from baseline was 13 beats per minute. After further treatment with SAVELLA 100 mg BID for two weeks, the mean increase from baseline in heart rate was 13 beats per minute. Similar trends were observed in the clinical trials where SAVELLA treatment was associated with mean increases in heart rate of approximately 7 to 8 beats per minute [see Adverse Reactions ( 6.1 ) ] . Increases in heart rate ≥ 20 beats per minute occurred more frequently in SAVELLA-treated patients when compared to placebo (8% in the SAVELLA 50 mg BID and 100 mg BID treatment arms versus 0.3% in the placebo arm). SAVELLA has not been systematically evaluated in patients with a cardiac rhythm disorder. Measure heart rate prior to initiating treatment and periodically monitor the heart rate throughout SAVELLA treatment. Treat pre-existing tachyarrhythmias and other cardiac disease before starting therapy with SAVELLA. For patients who experience a sustained increase in heart rate while receiving SAVELLA, either reduce the dose or discontinue treatment with SAVELLA if clinically warranted. 5.5 Seizures SAVELLA has not been systematically evaluated in patients with a seizure disorder. In clinical trials evaluating SAVELLA in patients with fibromyalgia, seizures/convulsions have not been reported. However, seizures have been reported infrequently in patients treated with SAVELLA for disorders other than fibromyalgia. SAVELLA should be prescribed with care in patients with a history of a seizure disorder. 5.6 Hepatotoxicity In the placebo-controlled fibromyalgia trials, increases in the number of patients treated with SAVELLA with mild elevations of ALT or AST (1-3 times the upper limit of normal, ULN) were observed. Increases in ALT were more frequently observed in the patients treated with SAVELLA 100 mg/day (6%) and SAVELLA 200 mg/day (7%), compared to the patients treated with placebo (3%). One patient receiving SAVELLA 100 mg/day (0.2%) had an increase in ALT greater than 5 times the upper limit of normal but did not exceed 10 times the upper limit of normal. Increases in AST were more frequently observed in the patients treated with SAVELLA 100 mg/day (3%) and SAVELLA 200 mg/day (5%) compared to the patients treated with placebo (2%). The increases of bilirubin observed in the fibromyalgia clinical trials were not clinically significant. No case met the criteria of elevated ALT > 3x ULN and associated with an increase in bilirubin ≥ 2x ULN. There have been cases of increased liver enzymes and reports of severe liver injury, including fulminant hepatitis with milnacipran from foreign postmarketing experience. In the cases of severe liver injury, there were significant underlying clinical conditions and/or the use of multiple concomitant medications. Because of underreporting, it is impossible to provide an accurate estimate of the true incidence of these reactions. Discontinue SAVELLA in patients who develop jaundice or other evidence of liver dysfunction. Treatment with SAVELLA should not be resumed unless another cause can be established. SAVELLA should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease. 5.7 Discontinuation of Treatment with SAVELLA Withdrawal symptoms have been observed in clinical trials following discontinuation of milnacipran, as with other SNRIs and SSRIs. During marketing of milnacipran, and other SNRIs and SSRIs, there have been spontaneous reports of adverse events indicative of withdrawal and physical dependence occurring upon discontinuation of these drugs, particularly when discontinuation is abrupt. The adverse events include the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe. Monitor patients for these symptoms when discontinuing treatment with SAVELLA. SAVELLA should be tapered after extended use. Do not abruptly discontinue. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate [see Dosage and Administration ( 2.4 )] . 5.8 Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including SAVELLA. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SNRIs, SSRIs, or SAVELLA. Also, patients taking diuretics or who are otherwise volume-depleted may be at greater risk [see Geriatric Use ( 8.5 )] . Consider discontinuation of SAVELLA in patients with symptomatic hyponatremia. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. 5.9 Increase d Risk of Bleeding Drugs that interfere with serotonin reuptake, including SAVELLA, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations ( 8.1 )]. Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Inform patients about the increased risk of bleeding associated with the concomitant use of SAVELLA and NSAIDs, aspirin, or other drugs that affect coagulation [see Drug Interactions ( 7.7 )] . 5.10 Activation of Mania No activation of mania or hypomania was reported in the clinical trials evaluating effects of SAVELLA in patients with fibromyalgia. However, those clinical trials excluded patients with current major depressive episode. Activation of mania and hypomania have been reported in patients with mood disorders who were treated with other similar drugs for major depressive disorder. As with these other agents, use SAVELLA cautiously in patients with a history of mania. 5.11 Patients with a History of Dysuria Because of their noradrenergic effect, SNRIs including SAVELLA, can affect urethral resistance and micturition. In the controlled fibromyalgia trials, dysuria occurred more frequently in patients treated with SAVELLA (1%) than in placebo-treated patients (0.5%). Caution is advised in use of SAVELLA in patients with a history of dysuria, notably in male patients with prostatic hypertrophy, prostatitis, and other lower urinary tract obstructive disorders. Male patients are more prone to genitourinary adverse effects, such as dysuria or urinary retention, and may experience testicular pain or ejaculation disorders. 5.12 Sexual Dysfunction Use of SNRIs, including SAVELLA, may cause symptoms of sexual dysfunction [see Adverse Reactions ( 6.1 , 6.2 )] . In male patients, SNRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SNRI use may result in decreased libido and delayed or absent orgasm. It is important for prescribers to inquire about sexual function prior to initiation of SAVELLA and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment. 5. 1 3 Angle Closure Glaucoma The pupillary dilation that occurs following use of SNRI drugs including SAVELLA may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. 5. 1 4 Concomitant Use with Alcohol In clinical trials, more patients treated with SAVELLA developed elevated transaminases than did placebo treated patients [see Warnings and Precautions ( 5.6 )] . Because it is possible that milnacipran may aggravate pre-existing liver disease, SAVELLA should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.